Mitochondrial dynamics, quality control and miRNA regulation in skeletal muscle: implications for obesity and related metabolic disease

Dahlmans, Dennis; Houzelle, Alexandre; Schrauwen, Patrick; Hoeks, Joris

doi:10.1042/cs20150780

Cited by 35 publications

(29 citation statements)

References 54 publications

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“…Their onset may however exacerbate oxidative stress and related metabolic cascades leading to insulin resistance and catabolism [21,22]. Potential reduction in ATP production may also directly result in low muscle strength and endurance capacity.…”

Section: Introduction: What We Knowmentioning

confidence: 99%

“…(3) Mitochondrial Dysfunction: Mitochondrial changes are not invariably observed in obese skeletal muscle until relatively late stages [21,22]. Their onset may however exacerbate oxidative stress and related metabolic cascades leading to insulin resistance and catabolism [21,22].…”

Section: Introduction: What We Knowmentioning

confidence: 99%

“…Complex metabolic and lifestyle abnormalities [17,18,19,20,21,22] as well as weight reduction therapies per se [23] may however also compromise the ability to preserve muscle function and mass. Skeletal muscle changes are not uniformly observed in obese individuals, and heterogeneous phenotypes may contribute to their underestimation.…”

Section: Introduction: What We Knowmentioning

confidence: 99%

“…(1) Cardiometabolic Complications: Complications such as metabolic syndrome or overt type 2 diabetes and hyperglycemia are associated with enhanced oxidative stress, pro-inflammatory changes, and mitochondrial dysfunction [21,29] that commonly cause catabolic abnormalities and may independently further muscle alterations. Altered tissue perfusion in the presence or absence of clinically relevant atherosclerotic disease as well as epicardial fat enlargement may also cause metabolic complications by enhancing ROS production and their negative metabolic impact [41,42].…”

Section: Introduction: What We Knowmentioning

confidence: 99%

“…In addition, several alterations have a negative impact on muscle quality in terms of strength per muscle unit and endurance capacity. The latter include muscle fat accumulation that reduces muscle density and quality with lower contractile protein content per unit tissue [35,53,54], mitochondrial dysfunction that may cause impaired ATP production, and maximal oxygen consumption leading to both reduced strength and endurance [21]. Physical inactivity that reduces muscle mass, mitochondrial biogenesis and function, and tissue lipid oxidation, also leads to reduced strength and endurance potentially enhancing tissue and systemic inflammation and oxidative stress [39,40,55].…”

Section: Introduction: What We Knowmentioning

confidence: 99%

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Sarcopenic Obesity: Time to Meet the Challenge

et al. 2018

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The prevalence of overweight and obesity has reached epidemic proportions worldwide due to increasingly pervasive obesogenic lifestyle changes. Obesity poses unprecedented individual, social, and multidisciplinary medical challenges by increasing the risk for metabolic diseases, chronic organ failures, and cancer as well as complication rates in the presence of acute disease conditions. Whereas reducing excess adiposity remains the fundamental pathogenic treatment for obese individuals, complex metabolic and lifestyle abnormalities as well as weight reduction therapies per se may also compromise the ability to preserve muscle function and mass, especially when chronic disease co-exists with obesity. Emerging evidence indicates that low muscle mass and quality have a strong negative prognostic impact in obese individuals and may lead to frailty, disability, and increased morbidity and mortality. Awareness of the importance of skeletal muscle maintenance in obesity is however low among clinicians and scientists. The term ‘sarcopenic obesity' has been proposed to identify obesity with low skeletal muscle function and mass, but its utilization is largely limited to the aging patient population, and consensus on its definition and diagnostic criteria remains insufficient. Knowledge on prevalence of sarcopenic obesity in various clinical conditions and patient subgroups, on its clinical impacts in patient risk stratification, and on effective prevention and treatment strategies remain therefore dramatically inadequate. In particular, optimal dietary options and medical nutritional support strategies to preserve muscle mass in obese individuals remain largely undefined. The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) recognize and indicate obesity with altered body composition due to low skeletal muscle function and mass (sarcopenic obesity) as a scientific and clinical priority for researchers and clinicians. ESPEN and EASO therefore call for coordinated action aimed at reaching consensus on its definition, diagnostic criteria, and optimal treatment with particular regard to nutritional therapy. We are convinced that achievement of these goals has a strong potential to reduce the burden of morbidity and mortality in the rapidly increasing obese patient population.

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Section: Introduction: What We Knowmentioning

confidence: 99%

Section: Introduction: What We Knowmentioning

confidence: 99%

Section: Introduction: What We Knowmentioning

confidence: 99%

Section: Introduction: What We Knowmentioning

confidence: 99%

Section: Introduction: What We Knowmentioning

confidence: 99%

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Sarcopenic Obesity: Time to Meet the Challenge

et al. 2018

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MicroRNA‐382 silencing induces a mitonuclear protein imbalance and activates the mitochondrial unfolded protein response in muscle cells

Dahlmans

Houzelle

Andreux

et al. 2018

Journal Cellular Physiology

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Proper mitochondrial function plays a central role in cellular metabolism. Various diseases as well as aging are associated with diminished mitochondrial function. Previously, we identified 19 miRNAs putatively involved in the regulation of mitochondrial metabolism in skeletal muscle, a highly metabolically active tissue. In the current study, these 19 miRNAs were individually silenced in C2C12 myotubes using antisense oligonucleotides, followed by measurement of the expression of 27 genes known to play a major role in regulating mitochondrial metabolism. Based on the outcomes, we then focused on miR‐382‐5p and identified pathways affected by its silencing using microarrays, investigated protein expression, and studied cellular respiration. Silencing of miRNA‐382‐5p significantly increased the expression of several genes involved in mitochondrial dynamics and biogenesis. Conventional microarray analysis in C2C12 myotubes silenced for miRNA‐382‐5p revealed a collective downregulation of mitochondrial ribosomal proteins and respiratory chain proteins. This effect was accompanied by an imbalance between mitochondrial proteins encoded by the nuclear and mitochondrial DNA (1.35‐fold, p < 0.01) and an induction of HSP60 protein (1.31‐fold, p < 0.05), indicating activation of the mitochondrial unfolded protein response (mtUPR). Furthermore, silencing of miR‐382‐5p reduced basal oxygen consumption rate by 14% ( p < 0.05) without affecting mitochondrial content, pointing towards a more efficient mitochondrial function as a result of improved mitochondrial quality control. Taken together, silencing of miR‐382‐5p induces a mitonuclear protein imbalance and activates the mtUPR in skeletal muscle, a phenomenon that was previously associated with improved longevity.

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MicroRNA‐204‐5p modulates mitochondrial biogenesis in C2C12 myotubes and associates with oxidative capacity in humans

Houzelle

Dahlmans

Nascimento

et al. 2020

Journal Cellular Physiology

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Using an unbiased high‐throughput microRNA (miRNA)‐silencing screen combined with functional readouts for mitochondrial oxidative capacity in C2C12 myocytes, we previously identified 19 miRNAs as putative regulators of skeletal muscle mitochondrial metabolism. In the current study, we highlight miRNA‐204‐5p, identified from this screen, and further studied its role in the regulation of skeletal muscle mitochondrial function. Following silencing of miRNA‐204‐5p in C2C12 myotubes, gene and protein expression were assessed using quantitative polymerase chain reaction, microarray analysis, and western blot analysis, while morphological changes were studied by confocal microscopy. In addition, miRNA‐204‐5p expression was quantified in human skeletal muscle biopsies and associated with in vivo mitochondrial oxidative capacity. Transcript levels of PGC‐1α (3.71‐fold; p < .01), predicted as an miR‐204‐5p target, as well as mitochondrial DNA copy number (p < .05) and citrate synthase activity (p = .06) were increased upon miRNA‐204‐5p silencing in C2C12 myotubes. Silencing of miRNA‐204‐5p further resulted in morphological changes, induced gene expression of autophagy marker light chain 3 protein b (LC3B; q = .05), and reduced expression of the mitophagy marker FUNDC1 (q = .01). Confocal imaging revealed colocalization between the autophagosome marker LC3B and the mitochondrial marker OxPhos upon miRNA‐204‐5p silencing. Finally, miRNA‐204‐5p was differentially expressed in human subjects displaying large variation in oxidative capacity and its expression levels associated with in vivo measures of skeletal muscle mitochondrial function. In summary, silencing of miRNA‐204‐5p in C2C12 myotubes stimulated mitochondrial biogenesis, impacted on cellular morphology, and altered expression of markers related to autophagy and mitophagy. The association between miRNA‐204‐5p and in vivo mitochondrial function in human skeletal muscle further identifies miRNA‐204‐5p as an interesting modulator of skeletal muscle mitochondrial metabolism.

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Mitochondrial dynamics, quality control and miRNA regulation in skeletal muscle: implications for obesity and related metabolic disease

Cited by 35 publications

References 54 publications

Sarcopenic Obesity: Time to Meet the Challenge

Sarcopenic Obesity: Time to Meet the Challenge

MicroRNA‐382 silencing induces a mitonuclear protein imbalance and activates the mitochondrial unfolded protein response in muscle cells

MicroRNA‐204‐5p modulates mitochondrial biogenesis in C2C12 myotubes and associates with oxidative capacity in humans

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